Sex-specific effects of ketogenic diet after pre-exposure to a high-fat, high-sugar diet in rats

• Published in: Nutrition, metabolism, and cardiovascular diseases Vol. 31; no. 3; pp. 961 - 971
• Main Authors: Sahagun, Elizabeth, Bachman, Brent B., Kinzig, Kimberly P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 10.03.2021
• Subjects: 3-Hydroxybutyric Acid - blood; Adiposity; Animals; Biomarkers - blood; Blood Glucose - metabolism; Corticosterone; Corticosterone - blood; Diet, High-Fat; Diet, Ketogenic; Dietary Sugars; Disease Models, Animal; Eating; Female; Glucose Intolerance - blood; Glucose Intolerance - diet therapy; Glucose Intolerance - etiology; Glucose Intolerance - physiopathology; Glucose tolerance; Ketogenic diet; Male; Obesity; Obesity - blood; Obesity - diet therapy; Obesity - etiology; Obesity - physiopathology; Rats; Rats, Sprague-Dawley; Sex differences; Sex Factors; Time Factors; Weight Gain; Glucose tolerance; Obesity; Sex differences; Corticosterone; Ketogenic diet
• ISSN: 0939-4753; 1590-3729
• DOI: 10.1016/j.numecd.2020.09.034

The objectives were to evaluate the relationship between ketogenic diets, the ketone body beta-hydroxybutyrate (BHB), parameters known to increase risk for cardiovascular and metabolic diseases in both sexes, using a pre-clinical model of obesity. Rats had access to a diet high in fat and sugar (HFS) for 12 weeks. After HFS, they switched to chow (HFS–CH) or ketogenic diet (HFS-KD) for 3 weeks to model a dietary intervention. Body weight, adiposity, and food intake were measured. Glucose tolerance and corticosterone response to stress were measured after HFS, then again after the intervention. Both sexes increased body weight, food intake, and adiposity compared to control (CTL) while on HFS. HFS females showed impaired glucose tolerance. HFS males developed a dampened corticosterone to stress, whereas HFS females developed an exacerbated response. The effects of HFS on adiposity and corticosterone were reversed in HFS–CH males. These same improvements were observed in HFS–CH females, although they still had impaired glucose tolerance. HFS-KD males showed some improvements, however, they still had higher body weight and adiposity than CTL. The same pattern was observed in females. These beneficial effects of KD correlated with plasma BHB levels in females but not in males. These data model effects reported in clinical literature and serve as a valuable translational tool to further test causal mechanisms that lead to desirable outcomes of KD. These sex-specific relationships are important, as KD could potentially affect endocrine mechanisms differently in males and females. •Access to diet high in fat and sugar (HFS) increases food intake, body weight, and adiposity in both sexes.•HFS dampens corticosterone stress response in males and exacerbates it in females; HFS also results in glucose tolerance impairments in females.•Deleterious metabolic effects of HFS are reversed in both sexes when access to HFS diet is restricted.•Ketogenic diet partially reverses metabolic disruption after HFS pre-exposure. Improvements correlate with ketone levels in females only.